Our long-term objective is to understand how neuromodulation and synaptic integration shape information processing in the olfactory system. This objective is addressed in the main olfactory bulb (MOB), the first central relay station for olfactory information. The endocannabinoid system is an important neuromodulatory system, which involves cannabinoid receptors, CB1R, and their endogenous activators, endocannabinoids (eCBs). In the MOB, neurons express high levels of CB1R, but its cellular and network functions are unknown. Our new preliminary data shows that CB1R agonists and antagonists alter the membrane potential and response to synaptic input of GABAergic interneurons, granule cells, and the membrane potential and firing pattern of principal neurons, mitral cells. Based on our preliminary data, the hypothesis is that eCBs prominently modulate membrane properties of MOB neurons, change the response to synaptic input, and regulate the neural network of the MOB. Consequently, the overall aim of this proposal is to determine the role of eCBs and CB1R for neural signaling in the MOB. In Specific Aim 1, the hypothesis will be tested that CB1R directly regulates the excitability of mitral cells and granule cells in a slice preparation of the mouse MOB. Do eCBs mediate self-inhibition of mitral cells and granule cells, i.e., are eCBs released by a neuron and target CBIRs on the same neuron? In Specific Aim 2, the hypothesis will be tested that CB1R regulates synaptic responsiveness of mitral cells and granule cells. Do eCBs serve as retrograde signaling molecules in the MOB between post- and presynaptic neurons to regulate presynaptic transmitter release? The interaction of the eCB system with another modulatory system, the metabotropic glutamate receptor (mGluR) system will be investigated to test the hypothesis that both systems are functionally interrelated. The experimental approach includes whole-cell patch-clamp recording and intracellular labeling of MOB neurons visualized with near infrared differential interference optics, use of mGluR knockout (KO) mice and CB1R KO mice, and characterization of cellular, membrane, pharmacologic and network properties of eCB-modulated neural processing in the MOB. Our findings help to explain the properties of marijuana at the cellular level through eCB-mediated synaptic processing in the MOB and eventually lead to a better understanding of drug addiction and could pave the way for new treatment strategies to prevent the use of drugs.